Polysaccharide-encapsulated bacteria cause substantial morbidity and mortality in young infants and other "high risk" groups. Antibody directed against capsular polysaccharide protects against these infections. Unfortunately, children less that two years of age, for unknown reasons, respond poorly to polysaccharide vaccines. Conjugation of bacterial polysaccharides to protein carriers improves the immunogenicity of these antigens, however different protein carriers elicit varying serum antibody concentrations and antibody of different functional activity. Furthermore, a large number of encapsulated bacteria cause human disease and individual vaccines must be developed for each. The aim of this project is to a) determine the relationship between antibody structure and functional activity and b) understand the molecular basis of the age-dependent - unresponsiveness to polysaccharide antigens. These findings will be invaluable in the design and assessment of vaccines directed against important bacterial pathogens. This is a five year project directed at the understanding of the role of important immunoglobulin variable region genes in determining fine antigen specificity and functional activity of anti-bacterial antibodies and the regulation of expression of these antibodies in early life. Specific aims include: (1) the determination of immunoglobulin structural components most important in defining fine antigen specificity of anti-bacterial polysaccharide antibodies, (2) definition of the role of heavy chain isotype and important immunoglobulin variable region genes in the functional activity of these antibodies, (3) determination of the ability of anti-polysaccharide antibody heavy chain/"surrogate" light chain complexes to bind antigen and, thus, influence the early antibody repertoire, and (4) the development of a transgenic mouse model in order to study the regulation of anti-polysaccharide antibodies in early development.